5/15/2018. Reduced Platelet Activity

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ASSOCIATION OF DESMOPRESSIN ACETATE ON OUTCOMES IN ACUTE INTRACRANIAL HEMORRHAGE IN PATIENTS ON ANTIPLATELET THERAPY Jessica McManus, Pharm. D. PGY2 Critical Care Pharmacy Resident UF Health Jacksonville Jessica.

edu These individuals have nothing to disclose concerning possible financial or personal relationships with commercial entities (or their competitors) that may be referenced in this presentation.

D., BCPS; Calvin Tucker 5, Pharm.D., BCPS, BCCCP; Randi Searcy 1, Pharm.D.; Michael Pizzi 1 D.O, Ph.D.; Katharina Maria Busl 6, M.D., M.S.; Michael Erdman 1, Pharm.D., BCPS 1 UF Health Jacksonville 2 Methodist University Health Center 3 OSU Wexner Medical Center 4 Medical University of South Carolina 5 St.

1 ASSOCIATION OF DESMOPRESSIN ACETATE ON OUTCOMES IN ACUTE INTRACRANIAL HEMORRHAGE IN PATIENTS ON ANTIPLATELET THERAPY Jessica McManus, Pharm. D. PGY2 Critical Care Pharmacy Resident UF Health Jacksonville These individuals have nothing to disclose concerning possible financial or personal relationships with commercial entities (or their competitors) that may be referenced in this presentation. Primary Investigator: Jessica McManus 1, Pharm. D. Co-Investigators: Jason Ferreira 1, Pharm.D., BCPS, BCCCP; G. Morgan Jones 2, Pharm.D., BCCCP, FCCM; Keaton Smetana 3, Pharm.D., BCCCP; Melanie Smith 4, Pharm.D., BCPS; Calvin Tucker 5, Pharm.D., BCPS, BCCCP; Randi Searcy 1, Pharm.D.; Michael Pizzi 1 D.O, Ph.D.; Katharina Maria Busl 6, M.D., M.S.; Michael Erdman 1, Pharm.D., BCPS 1 UF Health Jacksonville 2 Methodist University Health Center 3 OSU Wexner Medical Center 4 Medical University of South Carolina 5 St. Vincent s Healthcare 6 UF Health STUDY OBJECTIVE Describe desmopressin acetate s () effect on primary hemostasis in non-traumatic ICH with active antiplatelet therapy Antiplatelet Medications Primary prevention: Cerebrovascular and cardiovascular disease Secondary prevention: Stroke, myocardial infarction Medication Mechanism of action Duration of effect Aspirin Irreversibly inhibits COX-1 on platelets 7 10 days Clopidogrel Irreversibly inhibits ADP binding 5 days Prasugrel to P2Y12 receptor on platelet 5 9 days Ticagrelor Reversibly inhibits ADP binding to P2Y12 receptor on platelet 2 15 h Incidence of ICH in setting of antiplatelet therapy: % ICH: Intracranial hemorrhage COX: Cyclooxygenase, ADP: Adenosine diphosphate Anesthesiology 2014; 121: Reduced Activity Impact on ICH growth Poor prognostic factor Worse functional outcomes* at 3 months ICH & Reduced Activity Increased odds of death (up to 27%) Give platelets? ICH & Antiplatelet Medication Associated with worse outcomes PATCH trial Not recommended Give? Neurocritical care guidelines: may consider use *Modified Rankin Scale 3 5, 6 Stroke Jul;40(7): J Intensive Care Med Jan; 30(1) 3 7 : Desmopressin acetate Neurocrit Care Feb;24(1):6 46 1

2 Primary Hemostasis & Primary Hemostasis & V2 induces the release of vwf GPIb Endothelium damage exposes collagen fibrils GPIb receptors on platelets detect bound vwf V2 GPIb enhances platelet adhesion and activation by inducing the release of vwf vwf: von Willebrand factor Image adapted from immunopaedia.org J Thromb Haemost Jul;9 Suppl 1: Arterioscler Thromb Vasc Biol Mar;28(3): vwf: von Willebrand factor Image adapted from immunopaedia.org J Thromb Haemost Jul;9 Suppl 1: Arterioscler Thromb Vasc Biol Mar;28(3): Primary Literature: & Non Traumatic ICH & Function Assays 2 studies Focused on platelet function assays Inclusion ICH & received at least one dose of aspirin prior to ICH n=10 Acute ICH + known aspirin use or reduced platelet activity n=14 dose Primary outcome function test Conclusions 24 mcg n/a PFA 100TM Improved platelet function, but not significant 0.4 mcg/kg Change in platelet function (baseline to 1 h after start of ) Function Analyzer Epinephrine Statistically significant improved platelet activity Neurol Res Int 2014; 2014: ; Stroke 2014; 45: STUDY PURPOSE Compare outcomes in patients diagnosed with a non-traumatic ICH while on antiplatelet therapy based on administration Multicenter, IRB approved, retrospective, case-controlled study Primary site: UF Health Jacksonville (6 sites total) February 2012 to August

Study Endpoints STATISTICAL METHODS Primary Endpoint Composite of in hospital mortality or discharge to hospice care Secondary Endpoint Rate of hematoma expansion (>33% or 12.

3 Study Endpoints STATISTICAL METHODS Primary Endpoint Composite of in hospital mortality or discharge to hospice care Secondary Endpoint Rate of hematoma expansion (>33% or 12.5 ml from initial imaging) Rates of adverse events within 7 days of ICH diagnosis Hyponatremia Serum sodium <135 meq/l Thromboembolic event Myocardial infarction, deep vein thrombosis, pulmonary embolism, ischemic stroke Estimated 239 patients/group Estimated baseline mortality rate of 32% in non- recipients 20.5% rate of mortality/hospice rate in recipients Statistical Tests Continuous parametric data: Mann-Whitney U Nominal data: Chi-squared or Fisher s exact Two-tailed test utilized Statistical significance Crit Care Medicine, (1), supplement 1 Inclusion Criteria Age 18 years old Antiplatelet medication use documented 7 days prior to injury Diagnosed with an ICH per ICD-9/ICD-10 codes ICD-9: 431, 432.1, 432.9, , ICD-10: I61.0, I61.1, I61.2, I61.3, I61.4, I61.5, I61.6, I61.8, I61.9, I62.00, I62.01, I62.9, S06.300A, S06.369A, S06.9X0A Patient Selection Exclusion Criteria Admission to trauma service Confounding coagulopathy Anticoagulants or thrombolytics Thrombocytopenia Uremia International normalized ratio >1.5 dose other than mcg/kg Non-ICH indication for Withdrawal of care within 24 hours Subarachnoid hemorrhage (SAH) Craniotomy for hematoma evacuation Arteriovenous malformation (AVM) Patients Screened n=359 Patients Excluded Withdrawal of care, n=16 SAH, n=68 Thrombocytopenia, n=11 Trauma, n=63 Uremia, n=9 Indication, n=51 INR >1.5, n=8 Prior alteplase, n=48 AVM, n=6 Anticoagulation, n=30 Dose, n=3 Evacuation, n=31 Patients Included n=111 Patient Selection n=26 n=85 AVM: arteriovenous malformation, SAH: subarachnoid hemorrhage Ethnicity White African American Other 54 (63.5) 30 (35.3) 1 (1.2) 7 (26.9) 18 (69.2) 1 (3.8) 0.42 Male 52 (61.2) 16. (61.5) 0.97 Age* 73 [62 83] 65 [58 71] Antiplatelet medications Aspirin Clopidogrel DAPT Past Medical History DAPT: Dual antiplatelet therapy Hypertension Diabetes mellitus Ischemic stroke ICH 80 (94.1) 18 (21.2) 14 (16.5) 66 (77.6) 26 (30.6) 21 (24.7) 4 (4.7) 25 (96.2) 3 (11.5) 3 (11.5) 24 (92.3) 13 (50) 4 (15.4) 7 (6.3) Hospital LOS* (days) 8.9 [ ] 5.8 [ ] ICU LOS* (days) 2.7 [ ] 3.6 [ ] Days mechanically ventilated* 8 [6 14] 6 [4 10] Baseline Serum WBC* (thou/mm 3 ) 8.9 [ ] 8 [ ] Baseline Serum Mg* (mg/dl) 2 [ ] 1.9 [ ] Hypoglycemia within 24h of ICH diagnosis 3 (3.5) 0 (0) 1 Hyperglycemia within 24h of ICH diagnosis 16 (18.8) 6 (23.1) Baseline serum Na* (meq/l) 141 [ ] 141 [ ] Lowest serum Na 48 hourswithin 48h* (meq/l) 138 [ ] 137 [ ] Changes in serum Na* (meq/l) 0 [ 2.0 0] 1.5 [ ] s <100K/mm 3 within 7d of ICH diagnosis 2 (2.4) 2 (7.7) 0.23 LOS: Length of stay Hypoglycemia: BG <60 mg/dl; Hyperglycemia: BG >180 mg/dl 3

4 Treatment Characteristics Hospital Interventions ICH location Lobar Deep Subdural Intraventricular hemorrhage 1 32 (37.6) 41 (48.2) 12 (14.1) 21 (28.8) 6 (23.1) 19 (73.1) 1 (3.8) 12 (48.0) Modified Graeb Score* 4 [1 10] 6 [3 14] 0.17 ICH Score* 2 [1 3] 3 [1 3] 0.73 Initial IPH volume* (cm 3 ) 10.3 [ ] 8.3 [3.6 18] 0.58 Follow up IPH volume* (cm 3 ) 9.8 [ ] 9.2[ ] 0.77 Lowest GCS in 24h* 13 [8 14] 11 [6 14] Expressed as a percentage of intraparenchymal hemorrhages (lobar and deep) IPH: Intraparenchymal hemorrhage Time from initial CT to follow up CT* (h) 7.5 [5 18.5] [ ] Time from ICH identification to 3.92 [ ] administration* (h) Intracranial pressure monitoring 9 (10.6) 5 (19.2) Intraventricular alteplase 0 2 (7.7) Fresh frozen plasma 3 (3.5) 0 1 transfusion 4 (4.7) 7 (26.9) Packed RBC 1 (1.2) 1 (3.8) 0.37 Decompressive craniectomy 3 (3.6) 1 (3.8) 1 Seizure prophylaxis 42 (49.4) 10 (38.5) Hypertonic saline administration 18 (66.7) 9 (33.3) Hypertonic saline was defined as 3% NaCl Primary Outcome Secondary Outcomes Percent In Hospital Mortality or Hospice In Hospital Mortality Hospice p= In Hospital Mortality or Hospice p= In Hospital Mortality p= Hospice Hematoma expansion 1 12 (16.2) 6 (24) Adverse events 21 (24.7) 7 (26.9) 0.82 Thromboembolic 2 1 (1.2) 1 (3.8) Hyponatremia 3 19 (22.4) 6 (23.1) Outcome data are in n (%) 1 Hematoma expansion was defined as a >33% or 12.5 ml increase in hematoma volume. 2 Thromboembolic events included myocardial infarction, deep vein thrombosis, pulmonary embolism, and ischemic stroke. 3 Hyponatremia was defined as a serum sodium <135 STRENGTHS/LIMITATIONS CLINICAL IMPLICATIONS First study assessing the associated effects of on clinical outcomes in patients with non traumatic ICH in patients on antiplatelet therapy Limitations Preliminary data Underpowered Prescribing bias Confounding variables Retrospective did not show a therapeutic benefit There was no significant difference in rate of adverse effects Future use of in this patient population should be re-considered 4

5 SELF-ASSESSMENT How does effect primary hemostasis in patients taking antiplatelet medications? A. Increases GPIIb/IIIa activation B. Inhibits antiplatelet drugs through direct binding C. Increases levels of vwf and Factor VIII D. Inhibits platelet activation through thromboxane inhibition ASSOCIATION OF DESMOPRESSIN ACETATE ON OUTCOMES IN ACUTE INTRACRANIAL HEMORRHAGE IN PATIENTS ON ANTIPLATELET THERAPY Jessica McManus, Pharm. D. PGY2 Critical Care Pharmacy Resident UF Health Jacksonville 5

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